1. Field of the Invention
The present invention relates to some novel salts of aporphine compounds and methods for preparing the same and, more particularly, to pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents and methods for preparing the same.
2. Description of Related Art
A multitude of studies in experimental animals, together with clinical data, provide evidence that increased production of ROS (reactive oxygen species) are involved in the development and progression of cardiovascular disease including atherogenesis. In particular, the paper demonstrates various steps where oxidative stress could be involved in atherogenesis (Chen J et al., Indian Heart J 2004; 56: 163-173). Atherosclerosis is the buildup of fatty deposits called plaque on the inside walls of arteries. Arteries are blood vessels that carry oxygen and blood to the heart, brain, and other parts of the body. As plaque builds up in an artery, the artery gradually narrows and can become clogged. As an artery becomes more and more narrowed, less blood can flow through.
Oxidative stress refers to the physico-chemical, chemical, biochemical and toxicological behavior of the Reactive Oxygen Species (ROS). Oxidative stress plays a significant role in the pathogenesis of atherosclerosis and its complications. Oxidative stress mediates cell damage, in part, via reactive oxygen species (ROS). Oxidative stress has been identified throughout the process of atherogenesis. As the process of atherogenesis proceeds, inflammatory cells, as well as other constituents of the atherosclerotic plaque release large amounts of ROS, which further facilitate atherogenesis. In general, increased production of ROS may affect four fundamental mechanisms that contribute to atherosclerosis: endothelial cell dysfunction, vascular smooth muscle cells (VSMC) growth, monocyte migration and oxidation of low density lipoproteins (LDLs) (Alexander R W, Hypertension 1995; 25(2): 155-161; Berliner J A et al., Free Radic Biol Med 1996, 20: 707-727). A number of studies suggest that ROS oxidatively modified LDL is a more potent proatherosclerotic mediator than the native unmodified LDL (Heinecke J W., Atherosclerosis 1998, 141: 1-15). An important characteristic of endothelial dysfunction is impaired synthesis, release, and activity of endothelium-derived Nitric Oxide (NO). Nitric Oxide Synthase (NOS) converts Arginine into NO, the molecule that resists plaque formation, vasospasm, and abnormal clotting. Several studies have demonstrated that endothelial NO inhibits several processes involved in atherogenesis. For example, it mediates vascular relaxation and inhibits platelet aggregation, vascular SMC proliferation, and endothelium-leukocyte interactions. Inactivation of NO by superoxide anion limits the bioavailability of NO and leads to nitrate tolerance, vasoconstriction, and hypertension as well as atherosclerosis. Accordingly, if you can make and maintain Nitric Oxide then you will not develop cardiovascular disease. If the Nitric Oxide system can be successfully rebooted, then the cardiovascular disease can be stabilized.
ROS are involved in intracellular signalling. However, when ROS production is enhanced, dysregulation of physiological processes occurs. O2− and other radicals may react with NO and cause endothelial dysfunction. The reaction of O2− by NO leads to production of peroxynitrite. Peroxynitrite is itself a potent oxidant which can induce oxidation of proteins, lipids and DNA. In addition, ROS can stimulate vascular smooth muscle cell hypertrophy and hyperplasia. Furthermore, elevations in the levels of ROS may, via a variety of mechanisms, initiate development of a vascular pro-inflammatory state. This pro-inflammatory state may be promoted via activation of redox-sensitive transcription factors, such as nuclear factor B, the leucocyte adhesion molecule and vascular cell adhesion molecule 1, by reduction in levels of NO or by Angiotension-II-dependent pathways. Besides, risk factors for atherosclerosis, such as hypertension and hyperlipidemia, are also associated with increased generation of ROS (Patterson C et al., Circ. Res. 2000; 87(12): 1074-1076).
Oxidative stress alters many functions of the endothelium. As known in the art, oxidative stress is involved in the pathogenesis of a group of many diseases, such as cardiovascular diseases, including hypercholesterolemia, atherosclerosis, hypertension, diabetes, and heart failure etc. (Cai H et al., Circ Res. 2000; 87: 840-844), and ischemic cerebral diseases, including ischemic cerebral thrombosis, ischemic cerebral embolism, hypoxic ischemic encephalopathy etc. Department of Physiological Science, University of California also published that oxidative stress is thought to play a major role in the pathogenesis of a variety of human diseases, including atherosclerosis, diabetes, hypertension, aging, Alzheimer's disease, kidney disease and cancer (Roberts C K et al., Life Sci. 2009 Mar. 9). In addition, a role of the free-radical processes and disturbances of oxidative-restorative blood homeostasis and nervous tissue in the pathogenesis of brain ischemic pathology and other diseases was published (Solov'eva EIu et al., Zh Nevrol Psikhiatr Im SS Korsakova. 2008; 108(6): 37-42).
As ROS appear to have a critical role in many diseases, there has been considerable interest in identifying the enzyme systems involved and in developing strategies to reduce oxidative stress. Superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H (nicotinamide adenine dinucleotide phosphate reduced form) oxidase inhibitors are currently receiving much interest, while animal studies using gene therapy show promise, but are still at an early stage. Of the drugs in common clinical use, there is evidence that ACE (angiotensin-converting enzyme) inhibitors and AT1(angiotensin II type 1) receptor blockers have beneficial effects on oxidative stress above their antihypertensive properties, whereas statins, in addition to improving lipid profiles, may also lower oxidative stress (Hamilton C A et al., Clinical Science 2004; 106. 219-234).
Meanwhile, for some aporphine derivatives, the effect on oxidative stress has been investigated. Hereafter, some known aporphine derivatives (e.g. thaliporphine, glaucine, N-[2-(2-methoxyphenoxy)ethyl]norglaucine) will be introduced.
Thaliporphine is an aporphine derivative, which is a phenolic alkaloid isolated from the plants of Neolitsea konishii K (Teng C M et al., Eur J Pharmacol. 1993, 233(1). 7-12). It has been disclosed that thaliporphine is a positive inotropic agent with a negative chronotropic action. This compound has antiarrhythmic action. (Su M J et al., Eur. J Pharmacol. 1994; 254: 141-150).
In ischemia or ischemia-reperfusion (I/R), nitric oxide (NO) can potentially exert several beneficial effects. Thaliporphine increased NO levels and exerted cardioprotective action in ischemic or I/R rats. Thaliporphine treatment significantly increased NO and decreased lactate dehydrogenase (LDH) levels in the blood during the end period of ischemia or I/R. These changes in NO and LDH levels by thaliporphine were associated with a reduction in the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during ischemic or I/R period. Thaliporphine, acting via NO-dependent or NO-independent mechanisms, reduces ischemia or I/R-induced cardiac injury.
Thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha (Tumor necrosis factor alpha), NO and superoxide anion (O2−) (Chiao C W et al., Naunyn Schmiedebergs Arch Pharmacol. 2005; 371(1): 34-43).
The vasorelaxant effect of glaucine was studied. Glaucine has an intracellular effect and also acts on the cell membrane by blocking voltage-dependent and receptor-operated calcium channels (Loza I, Planta Med. 1993, 59(3): 229-231). The scavenging and iron-reducing properties of a series of benzylisoquinolines of natural and synthetic origin have been studied. Boldine and glaucine acted as scavengers of hydroxyl radical in the deoxyribose degradation by Fe3+-EDTA +H2O2 (Fenton's reagent) (Ubeda A et al., Free Radic Biol Med. 1993; 15(2): 159-167).
The antihyperglycemic actions of some aporphines and their derivatives in normal Wistar, streptozotocin (STZ)-induced diabetic (IDDM, Insulin-dependent diabetes mellitus) and nicotinamide-STZ induced diabetic (NIDDM, Non-insulin-dependent diabetes mellitus) rats were investigated. These compounds included thaliporphine, glaucine, boldine, and the derivatives, N-[2-(2-methoxyphenoxy)ethyl]norglaucine and diacetyl-N-allylsecoboldine. Thaliporphine exerts an antihyperglycemic action through insulin-dependent and insulin-independent mechanisms. Glaucine and boldine exerted less potent hypoglycemic action in STZ-diabetic rats. Both compounds may lower the plasma glucose mainly through an insulin-dependent mechanism. N-methyllaurotetanine and predicentrine produce their antihyperglycemic effect through an insulin-independent mechanism (Chi T C et al. Planta Med. 2006; 72(13): 1175-1180).
U.S. Pat. No. 6,313,134 discloses thaliporphine and its derivatives for the treatment and/or prophylaxis of cardiac diseases, including cardiac arrhythmia, myocardial ischemia or myocardial infarction, and sudden death caused by cardiac arrhythmia or acute myocardial infarction.
U.S. Pat. No. 7,057,044 provides aporphine and oxoaporphine compounds that have endothelial nitric oxide synthase (eNOS) maintaining or enhancing activities and may be used to manufacture a medicaments for preventing or treating ischemic diseases in human and mammal, and the ischemic diseases may include ischemic cerebral apoplexy, ischemic cerebral thrombosis, ischemic cerebral embolism, hypoxic ischemic encephalopathy, ischemic cardiac disease or ischemic enteropathy etc.
Aporphine and thaliporphine derivatives have the antihyperglycemic activities. Aporphine and thaliporphine derivatives may be used to prevent or treat hyperglycemic disease in human and mammal.
In addition to aporphine derivatives, some known carboxyl group-containing agents having effects on oxidative stress were disclosed as follows.
[Statins]
(a) Cardioprotective Actions of Statins
Statins increase NO bioavailability through PI3K/Akt (Phosphatidylinositol 3-kinase/Akt) and Rho-mediated signaling. NO can then mediate cytoprotection in the setting of myocardial ischemia and reperfusion through effects on the coronary vasculature and at the level of the mitochondria within cardiac myocytes. The vascular effects of increased NO bioavailability include the attenuation of both platelet and leukocyte adhesion and plugging within the coronary microcirculation and coronary vasodilatation. Statin-mediated generation of NO can also result in protection of the mitochondria through the activation of mitochondrial KATP (mKATP) channels. The opening of these channels serves to depolarize the mitochondrial membrane, maintain the integrity of the mitochondrial matrix and decrease ROS generation by the mitochondria following ischemia and reperfusion. With statins, a class of compounds is intended, comprising as main components fluvastatin, pravastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, lovastatin acid and simvastatin acid.
(b) Statins and Their Role in Vascular Protection
The statins reduce cholesterol synthesis through inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase and are widely prescribed for hyperlipidaemia to reduce the risk of atherosclerotic complications. The beneficial effect of lipid lowering by statins in the treatment of coronary heart disease has been demonstrated in large clinical trials. However, statins appear to have additional benefits on vascular function above and beyond their lipid lowering effects. Through inhibition of L-mevalonate synthesis, statins also prevent the synthesis of isoprenoid intermediates, including farnesylpyrophosphate and geranylgeranylpyrophosphate. Isoprenylation is important in the post-translational modification of a variety of proteins, including the small GTPases Rho, Rac and Ras, and hence plays an integral role in cellular signalling. Moreover, interference with isoprenylation underlies many of the beneficial actions of the statins on vascular endothelium, which include increased endothelial nitric oxide synthase expression, pro-angiogenic effects, increased fibrinolytic activity, immunomodulatory and anti-inflammatory actions, including increased resistance to complement. (Mason J C., Clinical Science 2003, 105: 251-266).
(c) Statins and Their Role in NO:
NO plays a central role in the maintenance of normal endothelial function and is generated in response to laminar shear stress. Endothelial NO is a vasodilator, inhibits smooth muscle proliferation, platelet aggregation, endothelial adhesion molecule expression and leucocyte-EC interactions. The demonstration that statins are able to enhance local NO generation in ECs, by increasing the half-life of eNOS (endothelial NO synthase) mRNA, was fundamental to the acceptance of the emerging evidence for lipid-independent effects. Statins retain their ability to increase eNOS in the presence of oxidized LDL and under hypoxic conditions. In addition, statins exert further beneficial effects on the endothelium through their inhibition of the expression of the potent vasoconstrictor endothelin-1. These actions have now been demonstrated for a number of different statins, including simvastatin, lovastatin, atorvastatin, pravastatin and fluvastatin in vivo and in vitro studies (Mason J C., Clinical Science 2003; 105: 251-266).
Atherosclerosis induced an endothelial [NO]/[ONOO−] balance indicative of endothelial dysfunction. Statins showed anti-atherosclerotic effects mediated by HO−1/eNOS, restoring the [NO]/[ONO O−] imbalance and reducing lipid peroxidation.
[Angiotensin II Receptor Blockers]
(a) Application of Angiotensin II Receptor Blockers
Angiotensin II receptor blockers (ARBs) can be employed for treating high blood pressure, and may be useful in the treatment of other cardiac diseases such as stroke, heart attack and congestive heart failure, and also seem to have a beneficial effect on the kidney, particularly the kidneys of people with diabetes.
Hypertension is an important risk factor in atherogenesis. There is activation of renin angiotensin system (RAS) in many hypertensive patients. Activation of RAS with the formation of angiotensin II (Ang II) and subsequent activation of Ang II receptors, mainly type I receptors (AT1R), has been implicated in atherogenesis. Ang II can exert multiple pro-atherogenic effects on vascular endothelial cells and smooth muscle cells(SMCs) by activating AT1R. Ang II enhances the uptake of ox-LDL and the biosynthesis of cholesterol in macrophages, leading to formation of foam cells; Ang II upregulates LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) gene and protein expression in cultured human coronary artery endothelial cells, and enhances the noxious effects of ox-LDL, both via AT1R activation. Ang II induces apoptosis of human coronary artery endothelial cells.
With angiotensin II receptor blockers (ARBs), a class of compounds is intended, comprising as main components losartan, valsartan, irbesartan, candesartan, telmisartan and olmesartan. Valsartan, candesartan and telmisartan are containing a carboxylic acid side chain. The pharmaceutical compositions containing them can be used as blood pressure-reducing drugs to treat and/or prevent stroke, heart attack and congestive heart failure and other cardiac diseases as cardiac arrhythmia, myocardial ischemia or myocardial infarction.
Ang II plays a crucial role in the induction of oxidative stress and the pathogenesis of cardiovascular and renal diseases, and the beneficial mechanisms of ARBs are multifactorial. (Shao J et al., J Hypertens. 2007; 25(8): 1643-1649.)
Telmisartan attenuated the oxidative stress induced by hydrogen peroxide in both cells, suggesting that it acted via a receptor-independent antioxidant effect. Telmisartan did not change expression levels of antioxidative enzymes such as catalase or glutathione peroxidase. Telmisartan inhibits intracellular oxidative stress, at least in part, in a receptor-independent manner, possibly owing to its lipophilic and antioxidant structure.
Several enzymatic sources of reactive oxygen species (ROS) were described as potential reasons of eNOS uncoupling in diabetes mellitus. Telmisartan inhibits activation of superoxide sources like NADPH oxidase, mitochondria, and xanthine oxidase. These effects may explain the beneficial effects of telmisartan on endothelial dysfunction in diabetes. (Wenzel P et al., Free Radic Biol Med. 2008, 45(5): 619-626.)
Cardioprotective mechanism of telmisartan is via PPAR-gamma-eNOS pathway in dahl salt-sensitive hypertensive rats. (Kobayashi N et al., Am J Hypertens. 2008; 21(5): 576-581) Telmisartan is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The cardioprotective mechanism of telmisartan may be partly due to improvement of endothelial function associated with PPAR-gamma-eNOS, oxidative stress, and Rho-kinase pathway.
[Angiotensin I Converting Enzyme Inhibitors]
(a) Application of Angiotensin I Converting Enzyme Inhibitors (ACEIs)
ACEIs are useful in the treatment of cardiovascular disorders, especially hypertension and congestive heart failure as well as for achieving other therapeutic effects by inhibiting the conversion of angiotensin I to angiotensin II.
With angiotensin I converting enzyme inhibitors, a class of compounds is intended, comprising as main components captopril, perindopri, ramipril, enalapril, fosinopril, quinapril, lisinopril, benazepril. The pharmaceutical compositions containing them are used for controlling blood pressure, treating heart failure and preventing kidney damage in people with hypertension or diabetes. They also benefit patients who have had heart attacks.
(b) Angiotensin I Converting Enzyme Inhibitors (ACEIs) and Their Role in Oxidative Stress and Cardiovascular Diseases
ACEI improve the vasoconstrictive/vasodilatory balance by blocking the formation of angiotensin II and preventing the degradation of bradykinin. In vitro, animal and human experimental studies have shown that ACEI have several properties: promote vasodilation, limit neurohormonal activation and vasoconstriction during ischemia, improve endothelial function by reducing oxidative stress, and slow down the development of atherosclerosis. Previous trials have shown that ACEI reduced cardiovascular events in patients with heart failure or ventricular dysfunction. In PROGRESS (n=6105), a perindopril-based regimen reduced recurrent stroke by 28% and substantially reduced cardiac outcomes among individuals with cerebrovascular disease. In HOPE (n=9297), ramipril reduced the composite outcome (cardiovascular death, myocardial infarction and cerebrovascular accident) by 22% in patients with high cardiovascular risk. (Bertrand M E., Curr Med Res Opin. 2004; 20(10):1559-69.)
Captopril has protective effects against damages of vascular endothelium induced by homocysteine and lysophosphatidylcholine. Captopril can prevent the inhibition of endothelium-dependent relaxation induced by homocysteine in isolated rat aorta, which may be related to scavenging oxygen free radicals and enhancing NO production (Fu Y F et al., J Cardiovasc Pharmacol. 2003, 42(4): 566-572).
The mechanisms of endothelial dysfunction induced by homocysteine thiolactone (HTL) may include the decrease of NO and the generation of oxygen free radicals and that captopril can restore the inhibition of endothelium-dependent relaxation (EDR) induced by HTL in isolated rat aorta, which may be related to scavenging oxygen free radicals and may be sulfhydryl-dependent (Liu Y H et al., J Cardiovasc Pharmacol. 2007; 50(2): 155-161).
Formation of homocysteine (Hcy) is the constitutive process of gene methylation. The accumulation of homocysteine (Hcy) leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased.
Hyperhomocysteinaemia is an independent risk factor for atherosclerosis, including cardiovascular (CV) disease, cerebrovascular disease and peripheral vascular disease in the general population. The homocysteine theory of atherosclerosis was first suggested by McCully in 1969, following his observation that children with homocysteinuria and markedly elevated plasma homocysteine levels (>100 μmol/L) had severe premature arterial disease. Since then, many clinical and epidemiological studies have demonstrated that a mild or moderate increase in plasma homocysteine is a risk factor for vascular disease.
The adverse effects of homocysteine on endothelial function may be mediated by reduced production and bioavailability of nitric oxide due to oxidative stress. Hyperhomocysteinaemia could cause oxidative stress via a number of mechanisms. In vitro studies using cultured endothelial cells have demonstrated auto-oxidation of homocysteine to form reactive oxygen species, including superoxide anion and hydrogen peroxide, increased lipid peroxidation and impaired production of the antioxidant glutathione peroxidase.[Fibric Acids](a)Application of Fibric Acids
Coronary heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events.
Fibric acid derivatives effectively lower triglycerides and raise high-density lipoprotein (HDL) cholesterol, but their effect on low-density lipoprotein (LDL) cholesterol is weakly beneficial (small decreases) to adverse (small increases) and varies according to the triglyceride level. With fibric acid, a class of compounds is intended, comprising as main components bezafibrate, clofibric acid, fenofibric acid and gemfibrozil.
(b) Fibric cids and Their Role in Oxidative Stress and Cardiovascular Diseases
The Bezafibrate Infarction Prevention (BIP) study was another randomized, placebo-controlled trial studying the effects of bezafibrate among men and women with coronary heart disease (CHD) (Circulation 2000; 102: 21-27). Bezafibrate therapy demonstrated significant reductions in triglyceride and LDL concentrations and fibrinogen while elevating HDL levels. When the study was completed, bezafibrate was associated with a 9% reduction (p=0.26) in fatal and nonfatal myocardial infarction and sudden death. Overall mortality rates and frequency of newly diagnosed cancer were similar among the groups, showing bezafibrate to be safe agent among adults with CHD, but it had no significant effect on the frequency of major coronary events.
Although there is evidence that hyperlipidemia and predominance of small dense low density lipoproteins (LDLs) are associated with increased oxidative stress, the oxidation status in patients with hypertriglyceridemia (HTG) has not been studied in detail. Bezafibrate reversed the oxidation resistance to the normal range. In conclusion, these results indicate the following: (1) Hypertriglyceridemia is associated with normal in vivo oxidative stress and enhanced ex vivo resistance of lipoproteins to oxidation. (2) Bezafibrate reduces the resistance of lipoproteins to copper-induced oxidation and enhances oxidative stress in hypertriglyceridemia patients (Arteriosclerosis, Thrombosis, and Vascular Biology. 2000, 20: 2434-2440).[Meglitinides](a) Application of Meglitinides
In type 2 diabetes mellitus, impairment of insulin secretion is an important component of the disease. The meglitinide analogues (“meglitinides”) are a class of oral antidiabetic agents that increase insulin secretion in the pancreas. The properties of this class of drug suggest that they have the potential to produce a rapid, short-lived insulin output. With meglitinide, a class of compounds is intended, comprising as main components repaglinide, nateglinide and mitiglinide. Two analogues are currently available for clinical use: repaglinide and nateglinide (Cochrane Database Syst Rev. 2007; 18(2): CD004654).
(b) Meglitinides and Their Role in Cardiovascular Protection
Glinides (meglitinides) represent a chemically heterogeneous new class of insulin-secreting agents characterized by a rapid onset and short duration of action. They act by closure of the ATP-dependant K channel. Repaglinide has an equivalent HbA1c lowering effect to conventional sulfonylureas but reduces predominantly postprandial glucose levels. Nateglinide has an even shorter duration of action and has almost no effect on fasting plasma glucose levels. Several experimental data suggest that glinides could preserve B cell function over time better than hypoglycaemic sulfonylureas, and that the improvement of post-prandial glucose levels could exert a long term protective cardiovascular effect (Diabetes Metab. 2006; 32(2): 113-120).
[Other Carboxyl Group-Containing Agents]
Other Carboxyl Group-Containing Agents and Their Role in Oxidative Stress and Induced Diseases
Atherosclerosis is a major cause of death in elderly individuals. Endothelial dysfunction is recognized as a key early event in atherogenesis. Administration of essential amino acids may improve brachial reactivity in elderly persons and may also protect against the development of atherosclerosis via the rise in plasma-free IGF-1 levels. (Manzella D et al., Am J Hypertens. 2005; 18(6): 858-863.)
The antioxidant supplement, n-acetyl cysteine, is a sulfur-based amino acid needed to synthesize glutathione, a natural antioxidant enzyme produced in the body to fight free-radical attack. Without glutathione, your body immune system would be greatly compromised, and left with little defense against toxins and disease.
N-acetyl cysteine may be effective in the prevention and/or treatment of cancer, heavy metal poisoning, smoker cough, bronchitis, heart disease, cystic fibrosis, acetaminophen poisoning, and septic shock. Its detoxifying effects may also help enhance the benefits of regular exercise by protecting the body from oxidative stress.
Acetylcysteine is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals. Recent studies suggest that high-dose N-acetylcysteine provides better protection from contrast-induced nephropathy, and the antioxidant properties of N-acetylcysteine may also provide cardiac protection. N-acetylcysteine-enhanced contrast medium reduces MI size and protects renal function in a pig model of ischemia and reperfusion. Thrombolysis after acute myocardial infarction may lead to a number of adverse effects (reperfusion injury) such as myocardial stunning, arrhythmias and even myocardial damage and extension of the infarct size. Some recent clinical studies have demonstrated that the intravenous infusion of N-acetylcysteine during thrombolysis was associated with a decrease in infarct size and better preservation of left ventricular function, probably due to antioxidant and free radical scavenger properties of N-acetylcysteine.
Methionine and cysteine enhance force of contraction by N-methylation of membrane phospholipids of the sarcolemma and sarcoplasmic reticulum. Methionine and, to a lesser extent, cysteine may reduce myocardial damage by oxygen radical species. (Pisarenko O I., Clin Exp Pharmacol Physiol. 1996; 23(8): 627-633.)
Amino acids (e.g. glutamate, aspartate), or keto acids (e.g. pyruvic acid, 2-ketoglutaric acid) have myocardial protective properties. Cardioplegic solutions rich in the hydrophilic, basic amino acids, glutamate and aspartate, or keto acids have enhanced myocardial preservation and left ventricular function. Several biochemical mechanisms exist by which certain amino acids may attenuate ischemic or reperfusion injury. Glutamate and aspartate may become preferred myocardial fuels in the setting of ischemia. They may also reduce myocardial ammonia production and reduce cytoplasmic lactate levels, thereby deinhibiting glycolysis. Some amino acids may become substrate for the citric acid cycle. Glutamate and aspartate also move reducing equivalents from cytoplasm to mitochondria where they are necessary for oxidative phosphorylation and energy generation. A rationale exists for the use of an amino acid-rich cardioplegia-like solution in myocardial infarction. (Clin Cardiol. 1998; 21(9): 620-624.) Pyruvate cardioplegia solution may be used in any surgery where the heart must be arrested, but it is particularly useful in cardiopulmonary bypass surgery. Because the solution relies primarily upon pyruvate to protect the heart from damage during and immediately after arrest, other additives are not as necessary as with current cardioplegia solutions or are not necessary at all. (US Patent Appl. 20030124503) Taurine (2-aminoethanesulphonic acid), a sulphur-containing amino acid, is found in most mammalian tissues. Taurine was found to exhibit diverse biological actions, including protection against ischemia-reperfusion injury, modulation of intracellular calcium concentration, and antioxidant, antiatherogenic and blood pressure-lowering effects. There is a wealth of experimental information and some clinical evidence available in the literature suggesting that taurine could be of benefit in cardiovascular disease of different etiologies. (Exp Clin Cardiol. 2008; 13(2): 57-65.) Taurine reduces iron-mediated myocardial oxidative stress, preserves cardiovascular function, and improves survival in iron-overloaded mice. The role of taurine in protecting reduced glutathione levels provides an important mechanism by which oxidative stress-induced myocardial damage can be curtailed. (Oudit G Y et al., Circulation. 2004; 109(15): 1877-1885.)
L-Arginine, the substrate of nitric oxide synthase, is known to exert favorable effects in the prevention and treatment of cardiovascular diseases. In several conditions, including atherosclerosis and ischemia/reperfusion, where oxygen metabolites are thought to mediate endothelial and myocardial injury, L-arginine has protective effects. (Lass A et al., Mol Pharmacol. 2002, 61: 1081-1088.) Nitric oxide (NO) plays a fundamental role in the vasculature because of its diverse influence in vascular protection, including its well-reported antiproliferative, anti-inflammatory, antithrombotic and vasodilator effects. In many vascular disease states, NO production is reduced as a result of endothelial dysfunction, in part caused by a decrease in substrate (L-arginine) availability. L-Arginine supplementation in patients with vascular disease is well reported to benefit patients therapeutically because of its effect on both NO-dependent and -independent mechanisms. The role of L-methionine and homocystine and their effect on NO also play an influential role in the body. (Huynh N N et al., Clin Exp Pharmacol Physiol. 2006, 33(1-2): 1-8)
The ability of carnosine to suppress significantly the development of ischemic reperfusion contracture and to support the restoration of the contractile force during reperfusion were shown. At the same time, a decrease of myoglobin and nucleoside release from myocytes was observed, this indicating a membrane-protecting effect of carnosine. Heart muscle protection by acetylated derivatives of carnosine and anserine under ischemia correlates with the preferential localization of these compounds in high quantities in the myocardium. (Alabovsky V V et al., Biochemistry (Mosc). 1997; 62(1): 77-87.)
Accumulating chemical, biochemical, clinical and epidemiological evidence supports the chemoprotective effects of phenolic antioxidants against oxidative stress-mediated disorders. The pharmacological actions of phenolic antioxidants stem mainly from their free radical scavenging and metal chelating properties as well as their effects on cell signaling pathways and on gene expression. (Soobrattee M A et al., Mutat Res. 2005; 579(1-2): 200-213.)
Scientific research has gradually verified the antidiabetic effects of ginger (Zingiber officinale Roscoe). Especially gingerols, which are the major components of ginger, are known to improve diabetes including the effect of enhancement against insulin-sensitivity. Aldose reductase inhibitors have considerable potential for the treatment of diabetes, without increased risk of hypoglycemia. The assay for aldose reductase inhibitors in ginger led to the isolation of five active compounds. 2-(4-hydroxy-3-methoxyphenyl)ethanoic acid, one carboxyl group-containing phenolic compound of the five active compounds, was a good inhibitor of recombinant human aldose reductase. These results suggested that it would contribute to the protection against or improvement of diabetic complications for a dietary supplement of ginger or its extract containing aldose reductase inhibitors. (Kato A et al., J Agric. Food Chem. 2006; 54(18): 6640-6644.)
Chromocarbe diethylamine is more effective than vitamin C against exercise-induced oxidative stress. Chromocarbe diethylamine was more effective than vitamin C in the prevention of glutathione oxidation in blood. Furthermore, chromocarbe diethylamine partially prevented muscle damage. Chromocarbe diethylamine was the most effective compound in the prevention of exercise-induced lipid peroxidation in plasma. (Pharmacol Toxicol. 2001; 89(5): 255-258.)